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Dogan Browning posted an update 6 months ago
Approximately one-fourth of autism spectrum disorder (ASD) cases are associated with a disruptive genetic variant. Many of these ASD genotypes have been described previously, and are characterized by unique constellations of medical, psychiatric, developmental, and behavioral features. Development of precision medicine care for affected individuals has been challenging due to the phenotypic heterogeneity that exists even within each genetic subtype. In the present study, we identify developmental milestones that predict cognitive and adaptive outcomes for five of the most common ASD genotypes. Sixty-five youth with a known pathogenic variant involving ADNP, CHD8, DYRK1A, GRIN2B, or SCN2A genes participated in cognitive and adaptive testing. Exploratory linear regressions were used to identify developmental milestones that predicted cognitive and adaptive outcomes within each gene group. We hypothesized that the earliest and most predictive milestones would vary across gene groups, but would be consistent acroat a child first starts walking and/or talking may help to better understand and support a child’s development who has a mutation to one of the above genes. Autism Res 2020, 13 1659-1669. © 2020 International Society for Autism Research and Wiley Periodicals LLC.Children with autism spectrum disorder (ASD) demonstrate heterogeneous writing skills that are generally lower than their typically developing (TD) peers and similar to peers with attention difficulties like attention-deficit/hyperactivity disorder (ADHD). Recent evidence suggests children with ASD spend less time engaging in writing tasks compared to their peers, but previous studies have not examined engagement specifically within the writing task environment. This study used video observation data collected from 121 school-age children (60 children with ASD, 32 children with ADHD, and 29 TD children) to compare differences in visual attention and writing task behaviors and relationships between task behaviors and age, cognitive skills, and ASD and ADHD symptom severity. Findings indicated that groups mostly spent time looking at and writing on the draft, though this was lowest in the ASD group. No differences were found between the ASD and ADHD groups after accounting for task behavior durations as percentdren with ASD compared to their peers and (b) moderate-to-strong relationships between writing scores and ASD symptom severity with within-task engagement in children with ASD and their peers with attention difficulties.Hepatobiliary cholesterol handling, mediated by Niemann-Pick C1-like 1 protein (NPC1L1) and ABCG5/8, is well-known to contribute to the homeostasis of cholesterol. We attempted to elucidate the impact of hepatobiliary cholesterol handling on the homeostasis of sphingolipids and lysophospholipids, especially sphingosine 1-phosphate (S1P). We induced the overexpression of NPC1L1 or ABCG5/8 in the mouse liver. Hepatic NPC1L1 overexpression increased the plasma and hepatic S1P levels, while it decreased the biliary S1P levels, and all of these changes were inhibited by ezetimibe. The ability of HDL to activate Akt in the endothelial cells was augmented by hepatic NPC1L1 overexpression. NPC1L1-mediated S1P transport was confirmed by both in vitro and in vivo studies conducted using C17 S1P, an exogenous S1P analog. Upregulation of apolipoprotein M (apoM) was involved in these modulations, although apoM was not necessary for these modulations. Moreover, the increase in the plasma S1P levels also observed in ABCG5/8-overexpressing mice was dependent on the elevation of the plasma apoM levels. In regard to other sphingolipids and lysophospholipids, ceramides were similarly modulated by NPC1L1 to S1P, while other lipids were differently influenced by NPC1L1 or ABCG5/8 from S1P. Hepatobiliary cholesterol handling might also regulate the functional lipids, such as S1P.
Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia.
Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4months of age. The tumour developed for 3weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2±0.861; wild-type LLC, 28.8±0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation.
Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.
Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the “complement” system would be broadly associated with memory function and associated brain structure. ML355 We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R2 change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant.
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